Laboratory of Molecular Nutrition for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China.
Lady Davis Institute for Medical Research and Department of Medicine, McGill University, Montreal, QC, H3T 1E2, Canada.
Cell Mol Life Sci. 2022 Jul 4;79(7):394. doi: 10.1007/s00018-022-04423-x.
Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters (zip14 and fpn1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.
铁是一种必需的微量元素，参与脊椎动物的多种生物活性。过量的铁积累已被确定为脂质沉积的重要介质。然而，其潜在机制尚不清楚。在本研究中，我们发现高铁饮食显著增加了肠道铁含量，并上调了两种铁转运蛋白（zip14 和 fpn1）的 mRNA 表达。肠道铁过载增加了脂肪生成，减少了脂肪分解，并促进了氧化应激和线粒体功能障碍。铁诱导的脂质积累是由缺氧诱导因子-1α（HIF1α）介导的，HIF1α是在抑制脯氨酰羟化酶 2（PHD2）后对线粒体氧化应激的反应而诱导的。从机制上讲，铁通过增强 HIF1α 与 pparγ 和 fas 启动子的 DNA 结合能力来促进脂质沉积。我们的研究结果提供了实验证据，表明氧化应激、线粒体功能障碍和 HIF1α-PPARγ 途径是铁诱导脂质沉积的关键介质。
